1. Rosasea and its Major Symptoms
Rosacea is a chronic skin disease that manifests redness and swelling, primarily on the face, especially on the central facial area. Other areas affected include the scalp, neck, ears, chest, back and the eyes. Rosacea is characterized by facial flushing, erythema, telangiectasia, and inflammatory episodes with papules and pustules and, in severe cases, rhinophyma. Comedones are notably absent1.
Patients with rosacea mostly have increased sensitivity of the facial skin and dry, flaking facial dermatitis, edema of the face, and persistent granulomatous papulonodules2. According to clinical and histopathologic features, the disease can be classified into 4 subtypes: (a) erythematotelangiectatic, (b) papulopustular, (c) phymatous, and (d) ocular, each with 3 grades of severity (mild, moderate, severe)3. The course of the disease is typically chronic, with recurrent remissions and relapses.
2. Other Red Face Related Skin Disorders
Rosacea is the most common red face skin disorder. Other red face related skin disorders, which share symptomatic similarities and probably pathological causes, include acne vulgaris, seborrheic dermatitis, photodermatitis and contact dermatitis. These red face related conditions may range from feelings of heat and sensitivity to flushing or burning with intense sensitivity4. Patients with rosacea and other red face related skin disorders often exhibit extreme sensitivity to environmental and topical factors5. Steroid-induced rosacealike dermatitis (or steroid rosacea) is a papular or pustular lesions with erythematous and edematous base with or without telangiectasia, which is caused by prolonged application of topical steroids to the face or as a rebound condition after discontinuation of topical steroids6,7 (Chen A Y Zirwas M J, 2009; Lee D H, Li K, Suh D H 2008). EGFR inhibitors, such as cetuximab, erlotinib, gefitinib, cause acneiform dermatitis on face or other skin area, including papulopustular reaction, erythema, telangiectasias, and flushing in 30 to 90% of patients and may also superinfected with bacteria, such as staphylococcus aureus8,9 (Wollenberg A, Kroth J et al, 2010; Lacouture M E, Maitland M L et al, 2010).
3. Pathogenesis of Rosacea
The etiology of rosacea is not well understood. Various factors have been suggested to contribute to the development and manifestation of rosacea. None of them, however, has been definitely confirmed1.
3.1. Genetic Contribution
Earlier studies have indicated genetic predisposition to flushing, the earliest manifestation of facial rosacea10. Additionally, glutathione S-transferase MU-1 (GSTM1) and glutathione S-transferase theta 1 (GSTT1) null genotype has been reported to be associated with an increased risk of rosacea11.
3.2. Inflammation and Innate Immune System
As rosacea progresses, inflammatory lesions become evident. Unlike acne vulgaris, inflammatory rosacea is not a bacterial disease of the pilosebaceous unit. Comedones are usually not present, and only normal bacterial flora is identified in skin samples taken from rosacea patients12. The inflammatory stage of rosacea can be regarded as a form of chronic sterile cellulitis13. While the presence of microorganisms has been examined as a potential contributing factor to rosacea, results have been inconclusive1. Demodex folliculorum mites are considered as commensal and do not play a significant pathogenic role in rosacea, although an inflammatory reaction to the mites may aggravate symptoms14.
Yamasaki et al found an abnormally high level of cathelicidins by histopathological staining in skin lesions from patients with rosacea. Human epidermal keratinocytes stimulated by cathelicidin peptides were found to increase the release of IL-8. Injection of cathelicidin peptides into the skin of mice caused inflammatory changes with increased neutrophil infiltration and microvessels characteristic of the skin disorder of rosacea in humans15. Cathelicdins possibly have dual roles in immunity because it can both kill microorganisms and stimulate host inflammatory responses such as inducing IL-8 release16. Other inflammatory cytokines found to be increased in rosacea include IL-1alpha and transforming growth factor beta-217,18.
3.3. Vascular Mediators
Inflammatory mediators may be responsible for the vasodilation seen in rosacea patients. For example, substance P, histamine, serotonin, bradykinin, or prostaglandins have been suggested19. Smith et al has reported an increased expression of vascular endothelial growth factor and its receptors in rosacea20.
4. Current Management of Rosasea
A number of antibiotics, such as tetracycline and doxycycline have been used in treating rosacea. It has been suggested that such antibiotics render anti-inflammatory rather than antimicrobacterial effects. However, other anti-inflammatory agents are not effective in treating rosacea. Immunosuppressive agents such as corticosteroids often worsen the inflammatory condition of rosacea1.
Topical metronidazole and certain systemic antibiotics are often used as first-line therapy for rosacea. Oral tetracycline, doxycycline, and minocycline are commonly used for treating rosacea. The efficacy of oral antibiotics is probably due more to anti-inflammatory rather than to antibiotic effects21. Azelaic acid 15% gel was approved by FDA of USA in 2002 for the topical treatment of mild to moderate rosacea22. Other traditional topical agents that have been used in a “off label” fashion include clindamycin, sulfacetamide and sulfur, but their mechanism is not well understood.
5. The Use of Berberine in Non-Skin Disorders
Berberine (Natural Yellow 18, 6-dihydro-9,10-dimethoxybenzo(g)-1,3-benzodioxolo (5,6-a) quinolizinium) is an isoquinoline alkaloid present in herb plants, such as coptis (Coptidis rhizome), phellodenron, Scutellaria baicalensis, Mahonia aquifolium and berberis23. Berberine and its derivatives have been found to have antimicrobial and antimalarial activities. It can act against various kinds of pathogens such as fungi, saccharomycete, parasite, bacterium and virus24. Berberine has been found to have other potential benefits. For example, it may have potential to treat high blood cholesterol, cardiovascular disease, diabetes, and tumor25.
Berberine also has anti-inflammatory function, yet the exact mechanism is unknown. Recently, some researcher reported that the anti-inflammatory mechanism of berberine is mediated through cyclooxygenase-2 (COX-2) pathway, since COX-2 plays a key role in the synthesis of prostaglandins, which is elevated in inflammation26. Berberine is used as an ingredient in some eye drop solution or eye ointment for the treatment of tracoma27.
6. The Use of Berberine in Skin Disorders
U.S. Pat. No. 6,440,465 pertains to topical skin formulations of glucosamine in an emollient base which contains berberine for the treatment of psoriasis28. Patent application #20050158404 pertains to a nutritional product, dietary supplement or pharmaceutical composition which contains vitamin A, vitamin E, selenium, vitamin B6, zinc, chromium, and a herbal source of berberine for the treatment of acne in oral administration29. U.S. Pat. No. 6,974,799 relates to topical compositions comprising a tripeptide (N-palmitoyl-Gly-His-Lys) and a tetrapeptide (N-palmitoyl-Gly-Gln-Pro-Arg) for the treatment of visible signs of aging including wrinkles, stretch marks, dark circles30. The formulation may contain additional ingredients, including berberine. In these inventions, berberine is included as one of the many ingredients and its concentration is not specified.
Patent application #20040146539 relates to topical neutraceutical compositions with body slimming and tone-firming anti-aging benefits that may be used to treat skin aging, skin wrinkle, skin exfoliating, acne, rosacea and other skin problems31. The composition of this invention includes antimicrobial agents selected from several agents including berberine. In these neutraceutical compositions, berberine is included as one of the many ingredients and its concentration is not specified. There has been a 10% Mahonia aquifolium cream (Relieva™, Apollo Pharmaceutical Canada Inc) containing 0.1% berberine for the treatment of psoriasis32.
The therapeutic effect of berberine in treating rosacea and other red face-related skin disorder is unknown. Until now, there is no direct evidence suggesting that berberine can improve the symptoms of rosacea.